A. Field of the Invention
The invention relates generally to the use of staphylococcal vaccines in preventing bacterial infection in an individual.
B. Description of the Related Art
Staphylococci and Enterococci rarely cause systemic infections in otherwise healthy individuals, and therefore are considered opportunistic pathogens. Through various mechanisms, normal adult humans and animals with a competent immune system attain an innate natural resistance to these bacterial infections. These include mucosal and epidermal barriers, in addition to possible immunological mechanisms. Interruption of these natural barriers as a result of injuries such as burns, traumas, or surgical procedures involving indwelling medical devices, increases the risk for staphylococcal and enterococcal infections. In addition, individuals with a compromised immune response such as cancer patients undergoing chemotherapy and radiation therapy, diabetes, AIDS, alcoholics, drug abuse patients, post organ transplantation patients and infants are at an increased risk for staphylococcal and enterococcal infections.
Staphylococci are commensal bacteria of the anterior nares, skin, and the gastrointestinal tract of humans. It is estimated that staphylococcal infections account for >50% of all hospital acquired infections. S. aureus alone is responsible for 15-25% of such infections and is surpassed only by S. epidermidis, which accounts for 35% of these infections. Staphylococcal infections, especially those caused by S. aureus are associated with high morbidity and mortality.
Staphylococcus and Enterococcus are a major cause of nosocomial and community-acquired infections, including bacteremia, metastatic abscesses, septic arthritis, endocarditis, osteomyelitis, and wound infections. For example, the bacteremia-associated overall mortality for S. aureus is approximately 25 percent. A study of hospitalized patients in 1995 found that death rate, length of stay, and medical costs were twice as high for S. aureus-associated hospitalizations compared with other hospitalizations. S. aureus bacteremia is a prominent cause of morbidity and mortality in hemodialysis patients with an annual incidence of three to four percent. Contributing to the seriousness of S. aureus infections is the increasing percentage of isolates resistant to methicillin, and early reports of resistance to vancomycin. Hence, immunoprophylaxis against S. aureus is highly desired.
The capsular polysaccharides (CPS) of S. aureus are virulence factors in systemic infections caused by this opportunistic pathogen. S. aureus CPS confer invasiveness by inhibiting opsonophagocytic killing by polymorphonuclear neutrophils (PMN), similar to other encapsulated bacteria, such as Streptococcus pneumoniae. This enables the bacteria to persist in the blood, where they elaborate several different virulence factors, including toxins and extracellular enzymes. Of the 13 known types of S. aureus, Types 5 and 8 account for approximately 85 percent of all clinical isolates. Nearly all of the remaining isolates are of Type 336 that carries a more recently identified polysaccharide (PS) antigen known as 336PS. Antibodies to Types 5 and 8 capsular polysaccharides (“T5CPS” and “T8CPS”) and 336PS induce type-specific opsonophagocytic killing by human PMNs in vitro, and confer protection against the homologous strain in animal infection models.
S. aureus causes several diseases by various pathogenic mechanisms. The most frequent and serious of these diseases are bacteremia and its complications in hospitalized patients. In particular, S. aureus can cause wound infections and infections associated with catheters and prosthetic devices. Serious infections associated with S. aureus bacteremia include osteomyelitis, invasive endocarditis and septicemia. Staphylococci have developed very sophisticated mechanisms for inducing diseases in humans, including both intracellular and extracellular factors. For instance, S. aureus possesses several surface antigens that facilitate its survival in the blood stream by helping the bacteria to evade phagocytic killing by the host leukocytes. These surface antigens include cell wall components such as teichoic acid, protein A, and capsular polysaccharides (CPS). Due in part to the versatility of these bacteria and their ability to produce extracellular products that enhance virulence and pathogenicity, staphylococcal bacteremia and its complications continue to be serious and frequently observed nosocomial infections.
Antibiotics such as penicillin have been used successfully against both staphylococcal and enterococcal infections in humans, but more recently the effectiveness of such antibiotics has been thwarted by the ability of bacteria to develop resistance. For example, shortly after the introduction of methicillin, the first semisynthetic penicillin, strains of methicillin-resistant S. aureus (MRSA) were isolated. Antibiotic resistance among staphylococcal isolates from nosocomial infections continues to increase in frequency, and resistant S. aureus strains continue to cause epidemics in hospitals in spite of developed preventive procedures and extensive research into bacterial epidemiology and antibiotic development. Enterococci resistant to vancomycin started to appear in 1988 and have now become commonplace among hospital-acquired infections. Although methicillin-resistant S. aureus organisms with intermediate resistance to vancomycin have been identified in some centers, it was only recently that three S. aureus strains with complete resistance to vancomycin were reported. This suggests that the probable conjugal transfer of vancomycin resistance from Enterococci to Staphylococci has become a reality, and dissemination of these strains could eventually lead to the widespread development of organisms that are more difficult to eradicate. The problem is compounded by multiple antibiotic resistance in hospital strains, which severely limits the choice of therapy.
The initial efficacy of antibiotics in treating and curing staphylococcal infections drew attention away from immunological approaches for dealing with these infections. Although multiple antibiotic-resistant strains of S. aureus have emerged, other strategies such as vaccines have not been developed. In addition, passive immunization has been tested for use in immune-compromised individuals, such as neonates, who are at increased risk for contracting these bacterial infections. The data failed to support a solid conclusion in recommending the use of passive immunization in this population. Baker et al., New Engl. J. Med. 35:213-219 (1992); Fanaroff et al., New Engl. J. Med. 330:1107-1113 (1994).
While polysaccharide vaccines have been developed for some primary bacterial pathogens that induce acute diseases in normal individuals, namely, Streptococcus pneumoniae, Neisseria meningitidis and Hemophilus influenzae, prior to development of StaphVAX® (Nabi Biopharmaceuticals, Rockville, Md.), none had been described specifically for protection against opportunistic bacteria.
StaphVAX® is a conjugate vaccine against two serotypes of S. aureus: Type 5 and Type 8. In the 1980s, eight different serotypes of S. aureus were identified using polyclonal and monoclonal antibodies to capsular polysaccharide (CPS). Karakawa et al., J. Clin. Microbiol. 22:445 (1985). (The contents of this document and all others listed herein are incorporated herein by reference in their entirety.) Surveys have shown that approximately 85% of isolates are capsular polysaccharide Type 5 or Type 8. More recently, Nabi Biopharmaceuticals has identified and patented an antigen, 336PS, which is found on newly discovered serotype Type 336 of Staphylococcus aureus. This serotype accounts for approximately 10-12 percent of all clinically significant S. aureus infections. In the present context, a “clinically-significant” bacterial strain is one that is pathogenic in humans. The antigen was identified, purified and characterized, and a prototype conjugate vaccine based on the antigen demonstrated the ability to protect animals from challenge with clinical isolates of the homologous serotype. Nabi Biopharmaceuticals is developing a second generation of StaphVAX® vaccine that will contain 336PS antigen in addition to S. aureus Types 5 and 8 antigens. These second-generation vaccines are expected to provide coverage for nearly 100% of all clinically significant S. aureus infections.
In addition to S. aureus, Staphylococcus epidermidis is another clinically significant Gram-positive bacterium that causes hospital-acquired infections. S. epidermidis PS1 Conjugate Vaccine is an investigational vaccine in clinical development for the prevention of S. epidermidis infections. This vaccine has been shown to induce antibodies that are protective in animal models and facilitate elimination of bacteria by the same type of immune system response as StaphVAX®.
Nabi's investigational S. epidermidis vaccine provides a solution for the problem of antibiotic resistance in S. epidermidis. However, there was no reason to expect that a vaccine based on this investigational vaccine would be effective in protecting individuals against infection by non-homologous strains of bacteria.